Human cytomegalovirus (CMV) has an intimate relationship with its human host, and disease is tightly linked to the immune status of infected persons. An understanding of how CMV induces and circumvents host immunity is of critical importance in efforts to combat CMV disease. In recent years, it was discovered that CMV virions stimulate, or repress, a large number of cellular genes. Most notably, cellular genes in the interferon stimulated gene (ISG) family were robustly induced. Our laboratory identified the viral component responsible for initiation of this cellular response as glycoprotein B (gB). Induction of ISGs by gB correlates with acquisition of an antiviral state. These observations point to gB as a CMV component with the capacity to activate the host innate immune response to infection. The long-term qoal of this research is to develop an understandinq of the mechanism by which CMV activates, and ultimately represses, innate immune responses. The central hypothesis of this proposal is that CMV glycoprotein(s) are subject to innate sensing in a manner similar to bacterial and fungal pathogens. Toll-like receptors (TLRs) are components of an ancient innate host defense that trigger cellular responses after recognition of inappropriate patterns on pathogens. We will directly test the hypothesis that the mechanism of initiation of the signaling response by gB is activation of a Toll-like receptor. This hypothesis is supported by preliminary data clearly implicating central signaling machinery in TLR pathways. A second area of investigation involves definition of the signal transduction pathway that leads to interferon responses. Our discovery that interferon responses are initiated from an extracellular viral signal reveals novel pathways for virus induction of innate responses. Other efforts are focused on the identification of CMV gene products involved in dampening the host response during virus replication. The final specific aim of this proposal will test the hypothesis that gB activated signal transduction events are a hallmark of CMV pathogenesis. Transcriptional profiling and characterization of gB-responsive signal transduction machinery will be determined in critical cell types in CMV pathology; endothelial cells and monocyte/macrophages. Given the significant role of host innate immune response in controlling viral infections and facilitating an adaptive host response, this work will potentially have impact in efforts to design improved CMV therapeutics. [unreadable] [unreadable]